There are two basic mechanisms for delivering exogenous agents, such as drugs and diagnostics, to certain types of body tissues. The most common is delivery via systemic administration.
In systemic administration, the agent is introduced into the systemic, or general, circulation by ingestion, injection, or inhalation. Circulating blood delivers the agent to the target tissue by either passive or active transport. The advantage to this method is that systemic administration, especially by ingestion, is simple. A disadvantage, however, is that the drug or medicament must be delivered at relatively high dosages in order to reach the targeted area in sufficient quantity. Moreover, the agent is delivered to the entire body, which can include sites where the agent may cause significant side effects. This is especially true for chemotherapeutic agents that tend to be toxic.
Another significant disadvantage is that certain tissues, such as brain or eye tissue, do not allow some types of chemicals to transfer well from the blood.
An alternative to systemic administration is to deliver the drug to the tissue by placing it directly into the tissue or in close proximity thereto. In order to deliver an agent directly to a specific tissue, there must first be a suitable deposit site. Preferably, this deposit site will be in close proximity to the targeted area.
A general example of this type of direct delivery method, is the injection of an agent to a site of pain, such as a muscle of the leg or arm or a particular joint. A more specific example of this type of direct delivery method is the introduction of slow release, drug-containing biocompatible particle implants directly into the anterior and/or posterior portions of the eye. Generally, these implants have been delivered into the vitreous humor of the eye via an intravitreal injection. While this is an effective method for delivering the agent to the targeted area with a reduced systemic loading, it carries a significant risk of damage to the tissues in the posterior portion of the eye. Furthermore, patient compliance for chronic administration is problematic due to the associated discomfort.
Another conventional example of this type of delivery to the eye is eyedrops delivered to the eye. Eyedrops act to deliver drugs directly to the anterior part of the eye by instillation into the cul de sac. The drugs are then moved from the tears of the eye across the cornea and into the anterior chamber without first entering the systemic circulation path. The advantage of this mode of delivery is that the drug is concentrated in the target tissue with a much lower systemic loading. This tends to reduce the above-mentioned systemic effects. The disadvantage of this type of administration is that not all tissues are accessible by this route of administration and tears may also remove a significant portion of the drug away from the targeted area relatively quickly.
Regardless of the method of delivery, drugs and other exogenous chemicals are cleared from any site of injection by a combination of mechanisms. Among these are: enzymatic degradation; diffusion into the surrounding tissue; and transport by the systemic circulation. Of these, transport by the systemic circulation is usually the most predominant mechanism. Accordingly, the deposit site should have a relatively low rate of clearance into the systemic circulation in order to reduce the systemic loading.
Many biological tissues, such as some layers of the walls of blood vessels and fallopian tubes, as well as the sclera of the eye, have relatively few cells and blood vessels and tend to exhibit properties which make them desirable deposit sites. These types of tissues are composed of intertwined fibers and fluid. As such, they are considered porous media in that the areas between the fibers form a continuous network of "channels" (interstitial space). These tissues also exhibit relatively low overall drug clearance rates because there is little or no enzymatic activity or blood flow, which leaves diffusion as the major elimination mechanism.
Thus, drugs deposited into these types of tissues will usually remain localized to the site of injection longer than in more cellular and vascularized tissues, such as the skin. The problem with these tissues, however, is that most of them are thin (e.g., from about 0.3 mm up to about 1.5 mm) and present numerous obstacles to injection within the thin tissue.
Generally, when an exogenous fluid is injected into a porous tissue, such as the sclera of the eye, the fluid must displace the endogenous fluid in the channel or interstitial space in the tissue. The rate at which exogenous fluid may be introduced into the tissue is inversely propositional to the resistance caused by the channels. In addition, when a needle is placed into a tissue, it creates a fluid path to the exterior of the tissue along the outer surface of the needle.
When making an injection, one consideration is the minimization of the leakage of fluid along this path to the exterior. In considering this leakage, it has been found that the resistance to fluid flow along the needle path is directly proportional to the length of the needle that is in contact with the tissue (i.e., length of the needle imbedded in the tissue). In considering the leakage, it has further been found that the ratio of the flow rate along the needle to the flow rate through the tissue is inversely proportional to the ratio of the respective resistances. Thus, it would be beneficial to increase the resistance to flow along the needle by increasing the penetration distance of the needle into the tissue. However, because of the inaccuracies and inherent variability with human intervention in controlling the penetration distance of the needle during such injections, control over the penetration distance of the needle, especially in thin tissues, presents numerous obstacles.
In drug delivery to the retinal or chordal region of the eye, numerous problems may be encountered. For example, with direct injection, choroidal hemorrhaging leading to retinal detachment may occur. In addition, with systemic administration, side effects and molecular size present problems that must be accommodated. Further, topical application to the cul de sac presents transport difficulties.
In addition, delivery of large molecules or particles (referred to herein as "large agents"), such as anti-bodies, viral vectors and the like, to the back of the eye (retina and choroid) is very difficult unless an injection is made directly into the vitreous humor of the eye. An alternative to such a method is to pierce the sclera at the back of the eye and make an injection directly to the retinal or choroidal tissues. As noted above, such procedures have substantial risk in causing damage to the ocular tissues. Moreover, delivery of these types of agents from a remote depot, such as the sclera or subconjunctival space is problematic because the agents tend to disperse very slowly from the site of injection.
Various approaches have been proposed to overcome the problems of injecting drugs or other therapeutic agents into the retina or choroidal regions. Generally, drugs have been delivered to the retina via the vitreous humor via an intravitreal injection. As noted above, while the method may be an effective method, it carries a significant risk of retinal detachment and/or infection. Furthermore, patient compliance for chronic administration is problematic due to the associated discomfort. Therefore, an alternate method of delivery is desirable, especially for the chronic delivery of either large molecules, such as proteins, anti-bodies, viral vectors, or drugs that have a high systemic toxicity.
A proposed method for delivering and withdrawing a sample to and from the retina is shown in U.S. Pat. Nos. 5,273,530 and 5,409,457. This device is for delivering a sample directly to the retina or subretinal region or withdrawing a sample therefrom. Although the device discloses a collar for regulating the depth the tip penetrates into the intraocular or subretinal region, the collar and tip are not adapted to prevent the penetration of the full thickness of the sclera and the choroid tissues in delivering the samples to the retina. Indeed, the device requires that the sclera and choroid be traversed by the tip prior to delivering or withdrawing the sample from the retina or subretinal region. Penetration into the choroid and retina can cause hemorrhage and possible retinal detachment. Moreover, the user must manipulate the tip, or needle through the ocular layers. Such imprecise movement could cause potential complications during the traversal of the ocular layers. Further, the device does not overcome the inaccuracies and variability which are inherent in injecting into a tissue wherein the path of the needle and movement of the needle is controlled by human intervention. Indeed, such inaccuracies may result in piercing the entire thickness of the thin layer tissue resulting in complications or may present drug delivery problems as described below.
Injections into thin tissues, such as the sclera of the eye or the walls of blood vessels, present problems for such a device. The penetration distance of the needle into the tissue is limited by the thickness of the tissue, the orthogonal approach of the needle to the tissue surface, and human control of the needle. Indeed, it is difficult for the user to control the angle and penetration distance of the needle in a free-handed manner, specifically into thin layer tissues.
For example, the sclera of the human eye generally varies from a thickness of about 0.3 mm to about 1.5 mm. Thus, injections made with a needle that is in a generally orthogonal relationship to the surface of the tissue are likely to fail due to fluid leakage from the site of injection or piercing the entire thin tissue thereby causing complications to underlying tissues or releasing the agent away from the targeted location.
In the case of scleral injection, the close proximity of the sclera to the retina means that a significant fraction of any agent injected into the intrascleral space may reach the retina by passive diffusion. There may be little direct elimination of any agent by either enzymatic degradation, clearance into the blood stream, or removal by tears due to the acellular and nonvascular nature of the sclera. Moreover, complications due to damaging the underlying choroid and retinal layers may be eliminated.
Another area which could benefit from direct injection is the wall of blood vessels especially those with atherosclerotic plaques. While access to the outer surface of many vessels is difficult, access to the inner surface of the vessel is not, there being a number of devices available for that purpose. However, delivery of therapeutic agents directly to these sites is problematic because the high rate of blood flow within the vessel tends to prevent exogenous agents from adhering to the inner surface. Systemic administration, while possible, is problematic because the region of tissue that would benefit from the therapeutic agent is small in relationship to overall size of the vasculature. Thus, the agent must be administered in great excess in order to achieve therapeutic efficacy.
The walls of certain blood vessels, especially those of the heart, are generally less than 1 mm thick. Precise placement within the wall is difficult. Insertion of a needle into the vessel wall can perforate the vessel causing hemorrhage into the surrounding tissue. In the vessels of the heart, such a perforation can be life threatening.
Devices for direct administration of fluids to the vasculature are known in the prior art. These rely on substantially orthogonal approaches to the inner wall of the vessel, the disadvantages of which have already been discussed above. In addition, these devices rely on an external reservoir for the medicament. A better method of injection where the needle is inserted farther into the tissue should reduce the amount of medicament that leaks from the site of injection. Furthermore, a device with a medicament reservoir deployed closer to the needle would require substantially smaller volumes of fluid and therefore less waste.
Thus, as set forth above, there is a need for an apparatus and method that reliably and safely facilitates injecting into a thin tissue, for example, the sclera, a therapeutic agent which is delivered either directly or allowed to diffuse to the targeted area, for example, the retina. There is a further need for a device that is effective for imbedding a needle in a guided injection at a predetermined penetration approach angle and penetration distance within the tissue such that a hydrodynamic seal between the tissue and the needle limits injected fluids from being expelled from the tissue due to the force of the injection. Furthermore, there is a need for a method for imbedding the needle at a penetration distance of greater than at least the thickness of the tissue without penetrating the full thickness of the tissue layer which could cause damage to underlying tissues. Moreover, there is a need for a safe and effective method and apparatus for delivering large molecules or particles, or large agents, such as anti-bodies, viral vectors, and the like, to the back of the eye, for example, the retina and choroid.